1,2-Dimethoxyethane → [5-(5-Ethyl-6-methoxy-2-methyl-pyridin-3-yl)-thiophen-2-ylmethyl]-carbamic acid tert-butyl ester

HRID 1921464Notes

Reaction equation

HRID 1921464 reaction equation
C[C:2]1(C)[C:7]([CH3:9])(C)[CH:6]=[N:5][C:4](B2OCCO2)=[CH:3]1.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+].[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][C:30]1[S:31]C(Br)=[CH:33][CH:34]=1)([CH3:25])([CH3:24])[CH3:23].[C:37](OCC)(=O)[CH3:38].[CH3:43]OCCOC>O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][C:30]1[S:31][C:9]([C:7]2[C:6]([CH3:43])=[N:5][C:4]([O:19][CH3:16])=[C:3]([CH2:37][CH3:38])[CH:2]=2)=[CH:33][CH:34]=1)([CH3:23])([CH3:24])[CH3:25]

Participants

8

Reactant 5

HCID 80711,2-DimethoxyethaneHCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 2779810tert-Butyl ((5-bromothiophen-2-yl)methyl)carbamateHCID 866103514,4,5,5-Tetramethyl-[1,3,2-dioxaborolan-2-yl)pyridine

Product 1

HCID 67492643[5-(5-Ethyl-6-methoxy-2-methyl-pyridin-3-yl)-thiophen-2-ylmethyl]-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

To a nitrogen flushed mixture of 3-ethyl-2-methoxy-6-methyl-5-(4,4,5,5-tetramethyl-[1,3,2-dioxaborolan-2-yl)pyridine (1.0 g, 3.6 mmol), cesium carbonate (3.52 g, 11 mmol), and (5-bromo-thiophen-2-ylmethyl)-carbamic acid tert-butyl ester (1.2 g, 4.0 mmol) in 1,2-dimethoxyethane (20 mL) and water (4 mL) is added palladium tetrakis(triphenylphosphine) (290 mg, 0.25 mmol) and the reaction mixture is heated to about 110° C. After maintaining the reaction mixture at 110° C. for 12 hr, the mixture is cooled, poured into ethyl acetate (50 mL) and washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with heptane-30% ethyl acetate to afford 0.98 g of [5-(5-ethyl-6-methoxy-2-methyl-pyridin-3-yl)-thiophen-2-ylmethyl]-carbamic acid tert-butyl ester. A solution of this ester in MeOH is then treated with saturated HCl in EtOAc (50 mL) and heated to about 75° C. After 6 hr at 75° C., the mixture is concentrated, and triturated with acetonitrile/water to afford 2.8 g of 5-(5-aminomethylthiophen-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one hydrochloride as a white solid (78% yield). LC/MS: RT 1.77 min; m/e 249 (M+H).

Workup

  1. customTo a nitrogen flushed
  2. temperatureAfter maintaining the reaction mixture at 110° C. for 12 hr
  3. temperaturethe mixture is cooled
  4. washwashed with water and brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue is chromatographed on SiO2
  9. washeluting with heptane-30% ethyl acetate

Sources & evidence

ORD record
ord-ac1cb3840ee14274a5b3a337fb8df171
Source dataset
uspto-grants-2012_05
Patent number
US08173682B2

Reaction notes

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